Evaluation of BR1 and BI30 AAVs for Brain Endothelial Tropism.

Brain endothelial cells are critical for homeostasis of the central nervous system. Novel adeno-associated viruses (AAV) with brain endothelial cell tropism have been developed and are beginning to be employed in mechanistic and therapeutic research. Studies using AAVs can be involved in terms of cost, time and personnel, and many groups, including our own, are not experts on the technology.

Loss of Endothelial Dysregulates Neural Function In Vivo.

Background: We recently found that loss of endothelial cell disrupts neurovascular and synaptic function. However, whether endothelial is detrimental or protective for neural function under physiological conditions is unknown. Therefore, the goal of this study was to determine the role of endothelial cell in regulating brain function in vivo.

Nonlipogenic ABCA1 Inducers (NLAI) for Alzheimer's Disease Validated in a Mouse Model Expressing Human .

Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because is the major genetic risk factor for Alzheimer's disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell-membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG).

Apolipoprotein E polymorphisms and female fertility in a transgenic mouse model of Alzheimer's disease.

Apolipoprotein E (APOE) is a major cholesterol carrier responsible for lipid transport and injury repair in the brain. The human APOE gene (h-APOE) has 3 naturally occurring alleles: ε3, the common allele; ε4, which increases Alzheimer's disease (AD) risk up to 15-fold; and ε2, the rare allele which protects against AD. Although APOE4 has negative effects on neurocognition in old age, its persistence in the population suggests a survival advantage.

Estradiol improves behavior in FAD transgenic mice that express but not after ovariectomy.

Increasing evidence suggests that female individuals have a higher Alzheimer's disease (AD) risk associated with post-menopausal loss of circulating estradiol (E). However, clinical data are conflicting on whether E lowers AD risk. One potential contributing factor is .

APOE2 Heterozygosity Reduces Hippocampal Soluble Amyloid-β42 Levels in Non-Hyperlipidemic Mice.

APOE2 lowers Alzheimer's disease (AD) risk; unfortunately, the mechanism remains poorly understood and the use of mice models is problematic as APOE2 homozygosity is associated with hyperlipidemia. In this study, we developed mice that are heterozygous for APOE2 and APOE3 or APOE4 and overexpress amyloid-β peptide (Aβ) (EFAD) to evaluate the effect of APOE2 dosage on Aβ pathology. We found that heterozygous mice do not exhibit hyperlipidemia.

A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3.

Background: Alzheimer's disease (AD) is characterized by cognitive dysfunction and amyloid plaques composed of the amyloid-beta peptide (Aβ). APOE is the greatest genetic risk for AD with APOE4 increasing risk up to ~ 15-fold compared to APOE3. Evidence suggests that levels and lipidation of the apoE protein could regulate AD progression.

genotype and sex modulate Alzheimer's disease pathology in aged EFAD transgenic mice.

Increasing evidence supports that age, and sex interact to modulate Alzheimer's disease (AD) risk, however the underlying pathways are unclear. One way that AD risk factors may modulate cognition is by impacting amyloid beta (Aβ) accumulation as plaques, and/or neuroinflammation Therefore, the goal of the present study was to evaluate the extent to which age, and sex modulate Aβ pathology, neuroinflammation and behavior . To achieve this goal, we utilized the EFAD mice, which express human or and have five familial AD mutations (FAD) that result in Aβ42 overproduction.

A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice.

Background: APOE genotype is the greatest genetic risk factor for sporadic Alzheimer's disease (AD). APOE4 increases AD risk up to 12-fold compared to APOE3, an effect that is greater in females. Evidence suggests that one-way APOE could modulate AD risk and progression through neuroinflammation.

Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation.

APOE4, encoding apolipoprotein E4 (apoE4), is the greatest genetic risk factor for Alzheimer's disease (AD), compared to the common APOE3. While the mechanism(s) underlying APOE4-induced AD risk remains unclear, increasing the lipidation of apoE4 is an important therapeutic target as apoE4-lipoproteins are poorly lipidated compared to apoE3-lipoproteins. ACAT (acyl-CoA: cholesterol-acyltransferase) catalyzes the formation of intracellular cholesteryl-ester droplets, reducing the intracellular free cholesterol (FC) pool.

The role of APOE in transgenic mouse models of AD.

Identified in 1993, APOE4 is the greatest genetic risk factor for Alzheimer's disease (AD), increasing risk up to 15-fold compared to the common variant APOE3. Since the mid 1990's, transgenic (Tg) mice have been developed to model AD pathology and progression, primarily via expression of the familial AD (FAD) mutations in the presence of mouse-APOE (m-APOE). APOE4, associated with enhanced amyloid-β (Aβ) accumulation, has rarely been the focus in designing FAD-Tg mouse models.

EFAD transgenic mice as a human relevant preclinical model of Alzheimer's disease.

Identified in 1993, is the greatest genetic risk factor for sporadic Alzheimer's disease (AD), increasing risk up to 15-fold compared with , with decreasing AD risk. However, the functional effects of on AD pathology remain unclear and, in some cases, controversial. In vivo progress to understand how the human (h)- genotypes affect AD pathology has been limited by the lack of a tractable familial AD-transgenic (FAD-Tg) mouse model expressing h- rather than mouse (m)- The disparity between m- and h-apoE is relevant for virtually every AD-relevant pathway, including amyloid-β (Aβ) deposition and clearance, neuroinflammation, tau pathology, neural plasticity and cerebrovascular deficits.

Behavioral and physiological characterization of PKC-dependent phosphorylation in the Grin2a∆PKC mouse.

Activity-dependent plasticity in NMDA receptor-containing synapses can be regulated by phosphorylation of serines and tyrosines in the C-terminal domain of the receptor subunits by various kinases. We have previously identified S1291/S1312 as important sites for PKC phosphorylation; while Y1292/Y1312 are the sites indirectly phosphorylated by PKC via Src kinase. In the oocyte expression system, mutation of those Serine sites to Alanine (that cannot be phosphorylated) in the GluN2A subunit, resulted in a decreased PKC stimulated current enhancement through the receptors compared to wild-type NMDA receptors.

Foraging decisions in wild versus domestic Mus musculus: What does life in the lab select for?

What does domestication select for in terms of foraging and anti-predator behaviors? We applied principles of patch use and foraging theory to test foraging strategies and fear responses of three strains of Mus musculus: wild-caught, control laboratory, and genetically modified strains. Foraging choices were quantified using giving-up densities (GUDs) under three foraging scenarios: (1) patches varying in microhabitat (covered versus open), and initial resource density (low versus high); (2) daily variation in auditory cues (aerial predators and control calls); (3) patches with varying seed aggregations. Overall, both domestic strains harvested significantly more food than wild mice.

Translocator protein 18 kDa negatively regulates inflammation in microglia.

Translocator protein 18 kDa (TSPO) is a mitochondrial outer membrane protein. Although TSPO expression is up-regulated during neuroinflammation, the role of TSPO and its signaling mechanisms in regulation of neuroinflammation remains to be elucidated at the molecular level. Here we demonstrate that TSPO is a negative regulator of neuroinflammation in microglia.

Brain region-specificity of palmitic acid-induced abnormalities associated with Alzheimer's disease.

Background: Alzheimer's disease (AD) is a progressive, neurodegenerative disease mostly affecting the basal forebrain, cortex and hippocampus whereas the cerebellum is relatively spared. The reason behind this region-specific brain damage in AD is not well understood. Here, we report our data suggesting "differential free fatty acid metabolism in the different brain areas" as a potentially important factor in causing the region-specific damage observed in AD brain.